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,
*
Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Department of Medicine, Harvard Medical School, Boston, MA 02215; Departments of
Pediatrics and
Laboratory Medicine/Pathology, University of Minnesota, Minneapolis, MN 55455;
§
Laboratoire de Génétique Humaine des Maladies Infectieuses, Faculté de Médecine Necker, Paris, France; and
¶
Department of Adult Oncology, Dana-Farber Cancer Institute, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115
IL-12 plays a pivotal role in the stimulation of immune responses
against intracellular infections. This role is manifested in the
increased susceptibility to atypical mycobacterial and salmonella
infections among individuals whose lymphocytes lack expression of
IL-12Rß1. Here, we report on a patient with Mycobacterium
avium infection, recurrent Staphylococcus aureus
sinusitis, and multiple adverse drug reactions whose T cells were
unable to produce IFN-
or proliferate in response to IL-12 despite
the expression of wild-type IL-12Rß1 and IL-12Rß2. The defect in
these functional responses to IL-12 was selective, as cytolytic
activity induced by IL-12 was intact, and lymphocytes were responsive
to stimulation by IL-2. An examination of cytokine signaling revealed
that STAT4 and extracellular regulated kinase 1 (ERK1) activation by
IL-12 was intact, whereas the activation of STAT1, -3, and -5 by IL-12
was lost. This impairment of STAT activation was specific for IL-12, as
STAT activation by IL-2, IL-15, and IFN- was unaffected. These
findings demonstrate that the activation of STAT4 alone is not
sufficient for IL-12-induced IFN- production and proliferation and
suggest that other STATs play a role in these responses to IL-12. While
the etiology of the impaired IL-12 signaling in this patient has not
yet been elucidated, the absence of mutations in IL-12Rß1 or
IL-12Rß2 and the preservation of STAT4 activation raise the
possibility that there may be a mutation in an as yet undiscovered
component of the IL-12 signaling complex that is normally required for
the recruitment and activation of STAT1, -3, and
-5.
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